Alpha 1-proteinase inhibitor (AlphalPi) is the major antiprot ease which regulates the activity of neutrophil elastase in the lower respiratory tract (LRT) of man. Persons genetically deficient in AlphalPi show increased susceptibility to pulmonary emphysema. In such persons the disease is though to result from uninhibited elastolytic attach upon alveolar connective tissue. We previously showed that lung AlphalPi is inactivated by cigarette smoking, so that the emphysema-component of chronic obstructive lung disease (COLD) in smokers may also be due, in part to an acquired imbalance between proteases and antiproteases in the LRT. Alpha 1-Pi inactivation by cigarette smoke appears to be based on oxidation of the inhibitor, and methionyl residues in AlphalPi (including one in the active site) are likely targets. Our research plan will explore the hypothesis that oxidative inactivation of AlphalPi in the lungs of smokers contributes to the association between cigarette smoking and COLD in man. (j) Alpha 1-Pi will be purified from bronchoalveolar washings of smokers vs non-smokers and analysed for its methionyl sulfoxide content. (2) Antioxidants which protect AlphalP8 in vitro against inactivation by myeloperoxidase -H2O2 coupled reactions will be tested in vivo for protection of lung AlphalPi against inactivation by inhaled cigarette smoke in experimental animals. (3) Experimental tobacco blends which deliver different amounts of the oxides of nitrogen will be compared for effects on lung AlphalPi activity in experimental animals. (4a) Inactivation of AlphalPi will be measured in bronchoalveolar washings of symptomatic smokers immediately after a standardized smoking exposure and the extent of inactivation correlated with physiologic and anatomic indices of small airway disease and emphysema, respectively. (4b) The same measurements will be carried out in asymptomatic smokers at repeated intervals over a five year period and the results correlated with functional indices of progressive airflow limitation in these subjects. (5) Finally, a new assay for elastin degradation products in urine developed by us will be tested for its ability to detect early lung damage in experimental animals treated with low doses of intrapulmonary elastase.